A new oral otoprotective agent. Part 1: Electrophysiology data from protection against noise-induced hearing loss (original) (raw)
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Uniform comparison of several drugs which provide protection from noise induced hearing loss
Journal of Occupational Medicine and Toxicology, 2010
Background: The ability of drugs to reduce noise induced hearing loss (NIHL) has been evaluated in diverse experimental conditions (animal species, noise intensities, durations, assessment techniques, etc), making it difficult to assess their relative efficacy. The present study was designed to provide more uniform comparisons and to allow to a better understanding of the mechanism of the NIHL. Methods: The drugs studied included furosemide (loop diuretic) and the antioxidants N Acetyl-L-Cysteine, vitamins A, C, E with the vasodilator magnesium. Mice were exposed to a continuous broadband noise (113 dB SPL for 3.5 hours) and the NIHL was assessed in all animals before noise exposure and 1 week after with auditory nerve brainstem evoked responses (ABR) to broadband clicks and to 8 kHz tone bursts.
Oxidative stress pathways in the potentiation of noise-induced hearing loss by acrylonitrile
Hearing Research, 2007
We hypothesize that the disruption of antioxidant defenses is a key mechanism whereby chemical contaminants can potentiate noise-induced hearing loss (NIHL). This hypothesis was tested using acrylonitrile (ACN), a widely used industrial chemical whose metabolism is associated with glutathione (GSH) depletion and cyanide (CN) generation. CN, in turn, can inhibit Cu/Zn superoxide dismutase (SOD). We have shown previously that ACN potentiates NIHL, even with noise exposure approaching permissible occupational levels. However, the relative involvement of GSH depletion and/or CN production in this potentiation is still unknown. In this study, we altered these metabolic pathways pharmacologically in order to further delineate the role of specific antioxidants in the protection of the cochlea. We investigated the effects of sodium thiosulfate (STS), a CN inhibitor, 4-methylpyrazole (4MP), a drug that blocks CN generation by competing with CYP2E1, and L-N-acetylcysteine (L-NAC), a pro-GSH drug, in order to distinguish between GSH depletion and CN production as the mechanism responsible for potentiation of NIHL by ACN. Long-Evans rats were exposed to an octave-band noise (97 dB SPL, 4 h/day, 5 days) and ACN (50 mg/kg). Separate pre-treatments with STS (150 mg/kg), 4MP (100 mg/kg) and L-NAC (4 · 400 mg/kg) all dramatically reduced blood CN levels, but only L-NAC significantly protected GSH levels in both the liver and the cochlea. Concurrently, only L-NAC treatment decreased the auditory loss and hair cell loss resulting from ACN + noise, suggesting that GSH is involved in the protection of the cochlea against reactive oxygen species generated by moderate noise levels. On the other hand, CN does not seem to be involved in this potentiation. Published by Elsevier B.V.
Acta otorhinolaryngologica Italica : organo ufficiale della Società italiana di otorinolaringologia e chirurgia cervico-facciale, 2006
Noise-induced hearing loss is one of the most common causes of deafness and, at present, there is no treatment for the recovery of the normal hearing threshold after prolonged exposure to loud acoustic stimuli and the generation of acoustic trauma. Prolonged exposure to noise can cause oxidative stress in the cochlea which results in the loss (via apoptotic pathways) of the outer hair cells of the organ of Corti. It has been demonstrated that some antioxidant molecules, for example L-N-acetyl-cysteine, can prevent oxidative stress in the inner ear. Aim of the study was to evaluate whether L-N-acetyl-cysteine, given at various dosages, can preserve the fine structures of the cochlea from the insult of continuous noise. A series of 18 Sprague Dawley male albino rats were exposed to continuous noise (8 kHz octave band noise, 105 dB SPL, 4 hours), and cochlear functionality was evaluated by recordings of transient evoked otoacoustic emissions and distortion products otoacoustic emission...
Antioxidant micronutrient impact on hearing disorders: concept, rationale, and evidence
American Journal of Otolaryngology, 2011
Purpose: Although auditory disorders are complex conditions, device-related modalities dominate current treatment. However, dysfunction from the central cortex to the inner ear apparatus is increasingly thought to be related to biochemical pathway abnormalities and to free radical-induced oxidative damage and chronic inflammation. Therefore, considering appropriate biologic therapy as an adjunct to standard care against these damaging factors may provide rational expansion of treatment options for otolaryngologists and audiologists. Methods: This review outlines the biologic concepts related to some auditory and vestibular conditions and details the current rationale for utilizing antioxidants for a spectrum of hearing disorders. The strategy is based on the authors' collective experience in antioxidant science and supported with published research, pilot animal data and preliminary clinical observations. Results: A comprehensive micronutrient approach was developed to exploit these pathways, and demonstrated safety and efficacy against oxidative damage and inflammation and clinically relevant neuroprotection. Cooperative research with Department of Defense institutions used prospective, randomized designs to show (1) reduction in oxidative damage measured in plasma and urine over six months, (2) protection against oxidative damage during 12 weeks of intense military training, (3) protection against inflammation after total body blast exposure (rodents), (4) strong neuroprotection against chemically-induced Parkinson's disease (rodents), (5) nerve VIII function improvement after concussive head injury in military personnel, and (6) tinnitus improvement in majority of patients after 90-day evaluation. Conclusion: This systematic review of biologic strategies against hearing disorders combined with new animal and human observations may provide a rational basis for expanding current practice paradigms.
Role of glutathione in protection against noise-induced hearing loss
Brain Research, 1998
. A potential mechanism of hearing loss due to acoustic overstimulation is the generation of reactive oxygen species ROS . ROS not removed by antioxidant defenses could be expected to cause significant damage to the sensory cells of the cochlea. We studied the Ž . w x Ž . influence of the antioxidant glutathione GSH on noise-induced hearing loss by using L-buthionine-S, R -sulfoximine BSO , an inhibitor Ž . of GSH synthesis, and 2-oxothiazolidine-4-carboxylate OTC , a cysteine prodrug, which promotes rapid restoration of GSH when GSH Ž . is acutely depleted. Pigmented female guinea pigs were exposed to broadband noise 102 dB SPL, 3 hrday, 5 days while receiving daily injections of BSO, OTC, or saline. By weeks 2 and 3 after noise exposure, BSO-treated animals showed significantly greater threshold shifts above 12 kHz than saline-treated subjects, whereas OTC-treated animals showed significantly smaller threshold shifts at 12 kHz than controls. Histologically assessed noise-induced damage to the organ of Corti, predominantly basal turn row 1 outer hair cells, was most pronounced in BSO-treated animals. High performance liquid chromatographic analysis showed that OTC significantly increased cysteine levels, but not GSH levels, in the cochlea. These findings show that GSH inhibition increases the susceptibility of the cochlea to noise-induced damage and that replenishing GSH, presumably by enhancing availability of cysteine, attenuates noise-induced cochlear damage. q 1998 Elsevier Science B.V.
Journal of Neuroscience, 2013
This study addresses the relationship between cochlear oxidative damage and auditory cortical injury in a rat model of repeated noise exposure. To test the effect of increased antioxidant defenses, a water-soluble coenzyme Q 10 analog (Q ter ) was used. We analyzed auditory function, cochlear oxidative stress, morphological alterations in auditory cortices and cochlear structures, and levels of coenzymes Q 9 and Q 10 (CoQ 9 and CoQ 10 , respectively) as indicators of endogenous antioxidant capability. We report three main results. First, hearing loss and damage in hair cells and spiral ganglion was determined by noise-induced oxidative stress. Second, the acoustic trauma altered dendritic morphology and decreased spine number of II-III and V-VI layer pyramidal neurons of auditory cortices. Third, the systemic administration of the water-soluble CoQ 10 analog reduced oxidative-induced cochlear damage, hearing loss, and cortical dendritic injury. Furthermore, cochlear levels of CoQ 9 and CoQ 10 content increased. These findings indicate that antioxidant treatment restores auditory cortical neuronal morphology and hearing function by reducing the noise-induced redox imbalance in the cochlea and the deafferentation effects upstream the acoustic pathway.
Glutathione limits noise-induced hearing loss
Hearing Research, 2000
The generation of reactive oxygen species (ROS) is thought to be part of the mechanism underlying noise-induced hearing loss (NIHL). Glutathione (GSH) is an important cellular antioxidant that limits cell damage by ROS. In this study, we investigated the effectiveness of a GSH supplement to protect GSH-deficient animals from NIHL. Pigmented guinea pigs were exposed to a 4 kHz octave band noise, 115 dB SPL, for 5 h. Group 1 had a normal diet, while groups 2, 3 and 4 were fed a 7% low protein diet (leading to lowered tissue levels of GSH) for 10 days prior to noise exposure. One hour before, immediately after and 5 h after noise exposure, subjects received either an intraperitoneal injection of 5 ml/kg body weight of 0.9% NaCl (groups 1 and 2), 0.4 M glutathione monoethyl ester (GSHE; group 3) or 0.8 M GSHE (group 4). Auditory thresholds were measured by evoked brain stem response at 2, 4, 8, 12, 16 and 20 kHz before and after noise exposure. Ten days post exposure, group 1 showed noise-induced threshold shifts of approximately 20 dB at 2, 16 and 20 kHz and 35 to 40 dB at other frequencies. Threshold shifts in group 2 were significantly greater than baseline at 2, 4, 16 and 20 kHz. GSHE supplementation in a dose-dependent fashion attenuated the threshold shifts in the low protein diet animals. Hair cell loss, as evaluated with cytocochleograms, was consistent with the auditory-evoked brainstem response results. Group 2 exhibited significantly more hair cell loss than any of the other groups; hair cell loss in group 3 was similar to that seen in group 1; group 4 showed less loss than group 1. These results indicate that GSH is a significant factor in limiting noiseinduced cochlear damage. This is compatible with the notion that ROS generation plays a role in NIHL and that antioxidant treatment may be an effective prophylactic intervention.
Toxicological Sciences, 2003
There is growing evidence that agents that produce oxidative stress in the cochlea have significant ototoxic potential by themselves and can potentiate noise-induced hearing loss as well. Acrylonitrile (ACN) metabolism entails conjugation with glutathione, resulting in rapid and pronounced depletion of this important antioxidant in many organs including brain, liver, and kidney. ACN metabolism also results in cyanide (CN) formation through a secondary oxidative pathway. The results of two physiological experiments are reported here. First, the acute effects of ACN (50 mg/kg sc) on auditory sensitivity are assessed using a within subject study. In the second study, persistent effects of ACN alone (50 mg/kg, sc and 2 ؋ 50 mg/kg, sc) and ACN in combination with noise exposure (8 h, 108 dB octave-band noise) are evaluated using threshold sensitivity as the dependent measure. Auditory threshold shift and absolute thresholds were determined using the compound action potential (CAP) amplitude. Acute ACN administration produces a loss in auditory threshold sensitivity that reached a maximum 10-20 min following sc injection. Auditory thresholds returned to control levels 75-100 min following exposure. In the study of permanent auditory threshold shifts, ACN plus noise increased auditory threshold impairment relative to rats receiving noise only when thresholds were assessed 3 weeks following exposure. ACN by itself did not produce permanent threshold impairment 3 weeks following administration. Assays were undertaken in separate groups of rats to track the elevation in blood CN and the depletion of total glutathione in cochlea, brain, and liver following ACN treatment. Systemic blood CN levels were not significantly elevated until 60-120 min following injection, and cochlear glutathione levels showed significant depletion as little as 15 min after injection and remained depressed for about 4 h. The results confirm the prediction that ACN is acutely ototoxic and can enhance noise-induced hearing loss.
Protective effects of N-acetylcysteine on noise-induced hearing loss in guinea pigs
Acta otorhinolaryngologica Italica : organo ufficiale della Società italiana di otorinolaringologia e chirurgia cervico-facciale, 2009
Increasing evidence suggests the involvement of oxidative stress in noise-induced hearing loss. The present study analysed, in an animal experimental model, the time course of the pathogenic mechanisms of noise-induced cochlear damage and the efficacy of the antioxidant drug N-acetylcysteine in reducing noise ototoxicity. Animals were divided into two groups, exposed to noise one treated with N-acetylcysteine for 3 days and one (the control group) with saline. Acoustic trauma was induced by a continuous pure tone of 6 kHz, at 120 dB SPL for 30 minutes. Electrocochleographic recordings were made from an implanted round window electrode and the compound action potentials were measured daily at 2-16 kHz for 7 days. Morphological changes were analysed by scanning electron microscopy. The acoustic threshold measured 1 hour after acoustic trauma was elevated in the control group to 70-90 dB in the higher frequencies of the compound action potential audiogram, with a maximum threshold elev...
N-acetylcysteine Treatment Reduces Noise-induced Hearing Loss in Guinea Pig
Journal of Community and Preventive Medicine, 2020
Introduction: Hearing loss is the most common form of sensory impairment in humans, affecting 5.3% worldwide population. Hearing impairment following cochlear damage due to noise trauma is linked to a molecular mechanism involving the formation of reactive oxygen species. Because increasing number of studies demonstrated that antioxidants may serve as effective compounds to block the activation of cochlear hair cell death and becoming feasible options for the treatment of several types of hearing loss. Here, we studied the effect of the antioxidant N-acetylcysteine (NAC) treatment on noise induced hearing loss in guinea pig. Results : We observed a permanent hearing loss and increase of prestin biomarker after acoustic trauma and we demonstrated that NAC treatment significantly reduced hearing loss when administrated daily by oral gavage. Conclusions: Our results suggest that antioxidants could be a pharmacological target for noise-induced hearing loss and that NAC can be used as a positive reference compound for new drug efficacy studies targeting hearing disorders.